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Substituted amide compound
8669246 Substituted amide compound
Patent Drawings:

Inventor: Kawaminami, et al.
Date Issued: March 11, 2014
Application:
Filed:
Inventors:
Assignee:
Primary Examiner: Saeed; Kamal
Assistant Examiner: Muresan; Ana Z
Attorney Or Agent: Oblon, Spivak, McClelland, Maier & Neustadt, L.L.P.
U.S. Class: 514/210.2; 514/105; 514/227.8; 514/230.5; 514/252.13; 514/274; 514/310; 514/326; 514/369; 544/58.2; 544/58.7; 546/169; 546/209; 546/269.7; 548/200
Field Of Search:
International Class: A61K 31/341; A61K 31/381; C07D 417/12; C07D 333/38; C07D 307/68; A61K 31/401; A61K 31/415; C07D 207/34; C07D 213/81; C07D 263/34; C07D 277/56
U.S Patent Documents:
Foreign Patent Documents: 101370794; 1 695 955; 2009 523774; 01 60819; 02 062389; 03 099765; 2004 002530; 2004 031118; 2005 058790; 2006 001463; WO 2010/051053; WO 2012/039460
Other References: Hama, K., et al., "Lysophosphatidic acid (LPA) receptors are activated differentially by biological fluids: possible role of LPA--bindingproteins in activation of LPA receptors," FEBS Letters, vol. 523, pp. 187-192, (2002). cited by applicant.
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Guo, C., et al., "Mitogenic Signaling in Androgen Sensitive and Insensitive Prostate Cancer Cell Lines," The Journal of Urology, vol. 163, pp. 1027-1032, (Mar. 2000). cited by applicant.
Allard, J., et al., "A rat G protein-coupled receptor selectively expressed in myelin-forming cells," European Journal of Neuroscience, vol. 10, pp. 1045-1053, (1998). cited by applicant.
Weiner, J.A., et al., "Lysophosphatidic Acid Receptor Gene vzg-1/1p.sub.A1/edg-2 Is Expressed by Mature Oligodendrocytes During Myelination in the Postnatal Murine Brain," The Journal of Comparative Neurology, vol. 398, pp. 587-598, (1998). cited byapplicant.
Weiner, J.A., et al., "Schwann cell survival mediated by the signaling phospholipid lysophosphatidic acid," Proceedings of the National Academy of Science, vol. 96, pp. 5233-5238, (Apr. 1999). cited by applicant.
Inoue, M., et al., "Initiation of neuropathic pain requires lysophosphatidic acid receptor signaling," Nature Medicine, vol. 10, No. 7, pp. 712-718, (Jul. 2004). cited by applicant.
Yanase, M., et al., "Lysophosphatidic Acid Enhances Collagen Gel Contraction by Hepatic Stellate Cells: Association with Rho-Kinase," Biochemical and Biophysical Research Communications, vol. 277, No. 1, pp. 72-78, (2000). cited by applicant.
Ikeda, H., et al., "Effects of Lysophosphatidic Acid on Proliferation of Stellate Cells and Hepatocytes in Culture," Biochemical and Biophysical Communications, vol. 248, No. 2, pp. 436-440, (1998). cited by applicant.
Watanabe, N., et al., "Both Plasma Lysophosphatidic Acid and Serum Autotaxin Levels are Increased in Chronic Hepatitis C," Journal of Clinical Gastroenterology, vol. 41, No. 6, pp. 616-623, (Jul. 2007). cited by applicant.
Watanabe, N., et al., "Plasma lysophosphatidic acid level and serum autotaxin activity are increased in liver injury in rats in relation to its severity," Life Sciences, vol. 81, pp. 1009-1015, (2007). cited by applicant.
Pradere, J.P., "LPA.sub.1 Receptor Activation Promotes Renal Interstitial Fibrosis," Journal of American Society of Nephrology, vol. 18, pp. 3110-3118, (2007). cited by applicant.
Tager, A.M., et al., "The lysophosphatidic acid receptor LPA.sub.1 links pulmonary fibrosis to lung injury by mediating fibroblast recruitment and vascular leak," Nature Medicine, vol. 14, No. 1, pp. 45-54, (Jan. 2008). cited by applicant.
Siess, W., et al., "Lysophosphatidic acid mediates the rapid activation of platelets and endothelial cells by mildly oxidized low density lipoprotein and accumulates in human atherosclerotic lesions," Proceedings of the National Academy of Science,vol. 96, pp. 6931-6936, (Jun. 1999). cited by applicant.
Imamura, F., et al., "Induction of In Vitro Tumor Cell Invasion of Cellular Monolayers by Lysophosphatidic Acid or Phospholipase D," Biochemical and Biophysical Research Communications, vol. 193, No. 2, pp. 497-503, (Jun. 15, 1993). cited byapplicant.
Xu, Y., et al., "Lysophosphatidic Acid as a Potential Biomarker for Ovarian and other Gynecologic Cancers," JAMA, vol. 280, No. 8, pp. 719-723, (Aug. 26, 1998). cited by applicant.
Hu, Y.L., et al., "Lysophosphatadic Acid Induction of Vascular Endothelial Growth Factor Expression in Human Ovarian Cancer Cells," Journal of the National Cancer Institute, Nol. 93, No. 10, pp. 762-768, (May 16, 2001). cited by applicant.
Kumar, A., et al., "Increased Pro-Nerve Growth Factor and p75 Neurotrophin Receptor Levels in Developing Hypothyroid Rat Cerebral Cortex Are Associated with Enhanced Apoptosis," Endocrinology, vol. 147, No. 10, pp. 4893-4903, (Oct. 2006). cited byapplicant.
Boucharaba, A., et al., "The type 1 lysophosphatidic acid receptor is a target for therapy in bone metastases," Proceedings of the National Academy of Science, vol. 103, No. 25, pp. 9643-9648, (Jun. 20, 2006). cited by applicant.
Jeon, E.S., et al., "Mesenchymal stem cells stimulate angiogenesis in a murine xenograft model of A549 human adenocarcinoma through an LPA1 receptor-dependent mechanism," Biochimica et Biophysica Acta, vol. 1801, pp. 1205-1213, (2010). cited byapplicant.
International Search Report Issued Nov. 22, 2010 in PCT/JP10/66572 Filed Sep. 24, 2010. cited by applicant.
American Urological Association Education and Research, Inc., Guideline on the management of benign prostatic hyperplasia (BPH), (2003). cited by applicant.
Zeng et al., Prostate, vol. 69 (2009) pp. 1-10. cited by applicant.
Hedlund and Andersson, Scan J Urol Nephrol, vol. 23 (1989) pp. 251-254. cited by applicant.
Aoki J., Semin Cell Dev Biol., vol. 15 (2004) pp. 477-489. cited by applicant.
Nitti V. W. Reviews in Urology, vol. 7 (2005) pp. S12-S17. cited by applicant.
Chang et al., International Journal of Urology, vol. 15 (2008) pp. 981-985. cited by applicant.
Boucharaba A. et al., PNAS, vol. 103, No. 25 (2006) pp. 9643-9648. cited by applicant.
Pradere et al., J Am Soc Nephrol, vol. 18 (2007) pp. 3110-3118. cited by applicant.
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Tager et al., Nature Medicine, vol. 14, No. 1 (2008) pp. 45-54. cited by applicant.
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Ma L. et al., J. Neurochem, vol. 109 (2009) pp. 603-610. cited by applicant.
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International Search Report issued on Dec. 6, 2011, in PCT/JP2011/071635 filed on Sep. 22, 2011. cited by applicant.
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Abstract: A substituted amide compound is useful as an active ingredient of a pharmaceutical composition, in particular a pharmaceutical composition for treating diseases caused by lysophosphatidic acid (LPA). The compound is of a formula: ##STR00001## In this formula, A is an optionally substituted aryl, etc.; B is an optionally substituted 5-membered aromatic hetero ring group; X is a single bond or --(CR.sup.X1R.sup.X2).sub.n--; n is 1, 2, 3, or 4; R.sup.X1 and R.sup.X2 are hydrogen, etc.; Y.sup.1 to Y.sup.5 are each CR.sup.Y or N; each R.sup.Y is hydrogen, etc.; R.sup.1 and R.sup.2 are hydrogen, etc.; m is 1, 2, or 3; R.sup.3 is hydrogen, etc.; and R.sup.4 is an optionally substituted lower alkyl, etc.
Claim: The invention claimed is:

1. A compound of the formula (I) or a salt thereof: ##STR00779## wherein A is aryl which may be substituted or an aromatic hetero ring group which may be substituted,B is a 5-membered aromatic hetero ring group which may be substituted, X is a single bond or --(CR.sup.X1R.sup.X2).sub.n--, n is 1, 2, 3, or 4, R.sup.X1 and R.sup.X2 are the same as or different from each other, and are H, halogen, OH, --O-- (lower alkylwhich may be substituted), or lower alkyl which may be substituted, or R.sup.X1 and R.sup.X2 are combined with each other to form oxo (.dbd.O), or R.sup.X1 and R.sup.X2 are combined with each other to form C.sub.2-5 alkylene which may be substituted, inwhich when n is 2, 3, or 4, R.sup.X1 may be combined with adjacent R.sup.X1 to form a new bond, Y.sup.1, Y.sup.2, Y.sup.3, Y.sup.4, and Y.sup.5 are the same as or different from each other, and are CR.sup.Y or N, R.sup.Y's are the same as or differentfrom each other, and are H, OH, halogen, --O-(lower alkyl which may be substituted), --S-(lower alkyl which may be substituted), lower alkyl which may be substituted, lower alkenyl which may be substituted, or cycloalkyl which may be substituted, R.sup.1and R.sup.2 are the same as or different from each other, and are H, halogen, --O-(lower alkyl which may be substituted), or lower alkyl which may be substituted, m is 1, 2, or 3, R.sup.3 is H, or lower alkyl which may be substituted, R.sup.4 is loweralkyl which may be substituted, lower alkenyl which may be substituted, cycloalkyl which may be substituted, aryl which may be substituted, a hetero ring group which may be substituted, or NR.sup.101R.sup.102, or R.sup.3 and R.sup.4 may be combined witheach other to form C.sub.2-5 alkylene which may be substituted, and R.sup.101 and R.sup.102 are the same as or different from each other, and are H, OH, --O-(lower alkyl which may be substituted), --C(.dbd.O)-(lower alkyl which may be substituted),--C(.dbd.O)--O-(lower alkyl which may be substituted), --NH--C(.dbd.O)-(lower alkyl which may be substituted), lower alkyl which may be substituted, lower alkenyl which may be substituted, cycloalkyl which may be substituted, aryl which may besubstituted, or a hetero ring group which may be substituted, or R.sup.101 and R.sup.102 may be combined with nitrogen atoms to which they are bonded to form nitrogen-containing monocyclic saturated hetero ring group, in which when R.sup.4 isNR.sup.101R.sup.102, at least one of R.sup.3, R.sup.101, and R.sup.102 is H.

2. The compound or a salt thereof according to claim 1, wherein A is phenyl which may be substituted with halogen, or a 5-membered aromatic hetero ring which may be substituted with halogen or lower alkyl, and R.sup.4 is lower alkyl which maybe substituted, cycloalkyl which may be substituted, aryl which may be substituted, or a nitrogen-containing hetero ring group which may be substituted, or NR.sup.101R.sup.102.

3. The compound or a salt thereof according to claim 2, wherein B is ##STR00780## L is S, and R.sup.L2 represents H, halogen, or lower alkyl which may be substituted with halogen or OH.

4. The compound or a salt thereof according to claim 3, wherein X is a single bond, Y.sup.1, Y.sup.2, Y.sup.3, Y.sup.4, and Y.sup.5 are CR.sup.Y, and R.sup.Y's are the same as or different from each other, and are H, OH, halogen, --O-(loweralkyl which may be substituted with halogen or --O-lower alkyl), lower alkyl which may be substituted with halogen or --O-lower alkyl, or cycloalkyl which may be substituted with halogen or --O-lower alkyl, R.sup.4 is lower alkyl (in which the loweralkyl may be substituted with halogen, OH, or --O--C(O)-lower alkyl), a 5-membered nitrogen-containing hetero ring group which may be substituted with lower alkyl, cycloalkyl, aryl, or NR.sup.101R.sup.102, and R.sup.101 and R.sup.102 are the same as ordifferent from each other, and are H, OH, O-(lower alkyl which may be substituted with halogen), lower alkyl (in which the lower alkyl may be substituted with halogen, OH, S-lower alkyl, or a hetero ring group), --C(.dbd.O)--O-(lower alkyl which may besubstituted with aryl), a hetero ring group which may be substituted with lower alkyl, or lower alkenyl, m is 3, and R.sup.1 and R.sup.2 are the same as or different from each other, and are H, halogen, --O-(lower alkyl which may be substituted withhalogen), or lower alkyl which may be substituted with halogen.

5. The compound or a salt thereof according to claim 4, wherein Y.sup.1, Y.sup.2, Y.sup.3, Y.sup.4, and Y.sup.5 are CR.sup.Y, and R.sup.Y's are the same as or different from each other, and are H, lower alkyl, or --O-(lower alkyl), and R.sup.3is H.

6. The compound or a salt thereof according to claim 5, wherein R.sup.4 is NR.sup.101R.sup.102, R.sup.101 is H, and R.sup.102 is H, O-(lower alkyl which may be substituted with halogen), lower alkyl (in which the lower alkyl may be substitutedwith halogen, OH, S-lower alkyl, or a hetero ring group), --C(.dbd.O)--O-(lower alkyl which may be substituted with aryl), a hetero ring group which may be substituted with lower alkyl, or lower alkenyl.

7. The compound or a salt thereof according to claim 5, wherein R.sup.4 is NR.sup.101R.sup.102, R.sup.101 is H, and R.sup.102 is lower alkyl, in which the lower alkyl may be substituted with halogen, OH, S-lower alkyl, or a hetero ring group.

8. The compound or a salt thereof according to claim 5, wherein R.sup.4 is NR.sup.101R.sup.102, R.sup.101 is H, and R.sup.102 is methyl which may be substituted with a group selected from Group G.sup.2, ethyl which may be substituted with agroup selected from Group G.sup.2, or propyl which may be substituted with a group selected from Group G.sup.2, in which Group G.sup.2 is halogen, OH, S-lower alkyl, or a hetero ring group.

9. The compound or a salt thereof according to claim 3, wherein X is a single bond, Y.sup.1, Y.sup.2, Y.sup.3, Y.sup.4, and Y.sup.5 are CR.sup.Y, and R.sup.Y's are the same as or different from each other, and are H, OH, halogen, --O-(loweralkyl which may be substituted with halogen or --O-lower alkyl), lower alkyl which may be substituted with halogen or --O-lower alkyl, or cycloalkyl which may be substituted with halogen or --O-lower alkyl, R.sup.3 is H, R.sup.4 is NR.sup.101R.sup.102,R.sup.101 and R.sup.102 are the same as or different from each other, and are H, --O-(lower alkyl which may be substituted with halogen), --C(.dbd.O)-(lower alkyl which may be substituted with halogen), --C(.dbd.O)--O-(lower alkyl which may besubstituted with halogen), lower alkyl which may be substituted with halogen or OH, or hetero ring which may be substituted with halogen or OH, or R.sup.101 and R.sup.102 are combined with nitrogen atoms to which they are bonded to form anitrogen-containing monocyclic saturated hetero ring, m is 3, and R.sup.1 and R.sup.2 are the same as or different from each other, and are H, halogen, --O-(lower alkyl which may be substituted with halogen), or lower alkyl which may be substituted withhalogen.

10. The compound or a salt thereof according to claim 9, wherein R.sup.4 is NR.sup.101R.sup.102, R.sup.101 is H, and R.sup.102 is H, methoxy, acetyl, methoxycarbonyl, methyl, ethyl, 2-fluoroethyl, 2-hydroxyethyl, or pyridin-2-yl.

11. The compound or a salt thereof according to claim 1, which is N-(aminosulfonyl)-2-{[(3,5-dimethoxy-4-methylbenzoyl)(3-phenylpropyl)amin- o]methyl}-1,3-thiazole-4-carboxamide; 5-chloro-2-{[(3,5-dimethoxybenzoyl)(3-phenylpropyl)amino]methyl}-N-(methy- lsulfonyl)-1,3-thiazole-4-carboxamide; 2-{[(3,5-dimethoxy-4-methylbenzoyl)(3-phenylpropyl)amino]methyl}-N-[(ethy- lamino)sulfonyl]-1,3-thiazole-4-carboxamide; 2-{[(3,5-dimethoxybenzoyl)(3-phenylpropyl)amino]methyl}-5-methyl-N-[(meth- ylamino)sulfonyl]-1,3-thiazole-4-carboxamide; 2-{[(4-ethyl-3,5-dimethoxybenzoyl)(3-phenylpropyl)amino]methyl}-5-methyl-- N-[(methylamino)sulfonyl]-1,3-thiazole-4-carboxamide; N-(dimethylsulfamoyl)-2-[({[1-(5-methoxypyridin-2-yl)cyclopropyl]carbonyl- }[3-(5-methyl-2-furyl)propyl]amino)methyl]-5-methyl-1,3-thiazole-4-carboxa- mide, or N-(dimethylsulfamoyl)-2-[([3-(3-fluorophenyl)propyl]{[1-(5-methox-ypyridin-2-yl)cyclopropyl]carbonyl}amino)methyl]-5-methyl-1,3-thiazole-4-c- arboxamide.

12. The compound or a salt thereof according to claim 11, which is N-(aminosulfonyl)-2-{[(3,5-dimethoxy-4-methylbenzoyl)(3-phenylpropyl)amin- o]methyl}-1,3-thiazole-4-carboxamide.

13. The compound or a salt thereof according to claim 11, which is 2-{[(4-ethyl-3,5-dimethoxybenzoyl)(3-phenylpropyl)amino]methyl}-5-methyl-- N-[(methylamino)sulfonyl]-1,3-thiazole-4-carboxamide.

14. The compound or a salt thereof according to claim 11, which is 2-{[(3,5-dimethoxy-4-methylbenzoyl)(3-phenylpropyl)amino]methyl}-N-[(ethy- lamino)sulfonyl]-1,3-thiazole-4-carboxamide.

15. A pharmaceutical composition comprising a compound or a salt thereof according to claim 12 and a pharmaceutically acceptable excipient.

16. A method for treating a disease caused by lysophosphatidic acid selected from the group consisting of benign prostatic hyperplasia, urinary dysfunction associated with benign prostatic hyperplasia, bladder neck sclerosis, and underactivebladder, comprising administering an effective amount of a compound or a salt thereof according to claim 11 to a subject in need thereof.

17. A method for treating a disease caused by lysophosphatidic acid selected from the group consisting of breast cancer, chronic renal diseases associated with fibrosis and idiopathic pulmonary fibrosis, comprising administering an effectiveamount of a compound or a salt thereof according to claim 11 to a subject in need thereof.

18. A method for treating urinary dysfunction associated with benign prostatic hyperplasia, comprising administering an effective amount of a compound or a salt thereof according to claim 12 to a subject in need thereof.

19. A method for treating urinary dysfunction associated with benign prostatic hyperplasia, comprising administering an effective amount of a compound or a salt thereof according to claim 13 to a subject in need thereof.

20. A method for treating urinary dysfunction associated with benign prostatic hyperplasia, comprising administering an effective amount of a compound or a salt thereof according to claim 14 to a subject in need thereof.

21. A method for treating urinary dysfunction associated with benign prostatic hyperplasia, comprising orally administering an effective amount of a compound or a salt thereof according to claim 12 to a subject in need thereof.

22. A method for treating urinary dysfunction associated with benign prostatic hyperplasia, comprising orally administering an effective amount of a compound or a salt thereof according to claim 13 to a subject in need thereof.

23. A method for treating urinary dysfunction associated with benign prostatic hyperplasia, comprising orally administering an effective amount of a compound or a salt thereof according to claim 14 to a subject in need thereof.

24. A method for treating benign prostatic hyperplasia, comprising administering an effective amount of a compound or a salt thereof according to claim 12 to a subject in need thereof.

25. A method for treating benign prostatic hyperplasia, comprising administering an effective amount of a compound or a salt thereof according to claim 13 to a subject in need thereof.

26. A method for treating benign prostatic hyperplasia, comprising administering an effective amount of a compound or a salt thereof according to claim 14 to a subject in need thereof.
Description:
 
 
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